Lanthanum carbonate hydrate, which has been used to treat hyperphosphatemia (see, e.g., U.S. Pat. No. 5,968,976) and hyperphosphatemia in patients with renal failure (see, e.g., JP 1876384), is a molecule which is prone to decarboxylation under certain stressful conditions such as high heat and elevated humidity. These conditions may be present during the manufacture of lanthanum carbonate hydrate or during the storage of the unformulated or formulated material. The decarboxylation product is lanthanum hydroxycarbonate.
Hyperphosphatemia is a particular problem of patients with renal failure, using dialysis equipment. Conventional dialysis fails to reduce levels of phosphate in the blood, so that the levels rise in time. It is known to control phosphate levels by the oral administration of aluminium salts, or calcium salts. With the known toxic effects of aluminium, aluminium-based therapy tends to be avoided. In the case of calcium salts, calcium is absorbed rather readily from the gut, and in turn causes hypercalcaemia.
Certain forms of lanthanum carbonate have been used to treat hyperphosphatemia in patients with renal failure (see, e.g., JP 1876384). U.S. Pat. No. 5,968,976, owned by the assignee of the present invention, describes the preparation and use in a pharmaceutical composition of certain hydrates of lanthanum carbonate for the treatment of hyperphosphatemia.
U.S. Pat. No. 5,968,976 teaches that certain forms of lanthanum carbonate exhibit improved performance in a variety of tests, over standard commercial lanthanum carbonate, which is believed to be the octahydrate form, and over La2(CO3)3xH2O or similar compounds. U.S. Pat. No. 5,968,976 teaches the use of lanthanum carbonate of formula La2(CO3)3xH2O where x has a value from 3 to 6, preferably from 3.5 to 5, more especially from 3.8 to 4.5, for the preparation of a medicament for the treatment of hyperphosphatemia by administration into the gastrointestinal tract. Also provided is a pharmaceutical composition comprising said lanthanum carbonate, in admixture or association with a pharmaceutically acceptable diluent or carrier, in a form for administration into the gastrointestinal tract for the treatment of hyperphosphatemia. Also provided is a method of treatment of hyperphosphatemia in a patient with renal failure, comprising the administration of an effective dose of said lanthanum carbonate into the gastrointestinal tract. Also provided is administration by an oral route.
It is a regulatory requirement that analytical methods be developed to quantify the amount of degradation products which may be present in a pharmaceutical agent and a pharmaceutical product. Typically, this is done using a chromatographic technique such as high performance liquid chromatography (HPLC), which requires dissolution of test samples in the appropriate solvent.
Both La2(CO3)3 and LaCO3OH are insoluble in water and standard organic solvents. Either may be dissolved in acidic solution, but in doing so, reactions occur which form impurities in the sample. For example, dissolution of either La2(CO3)3 or LaCO3OH in aqueous hydrochloric acid results in a solution of lanthanum chloride, (LaCl3). Since both materials give the same product after dissolution of a sample in acid, there is no way to distinguish La2(CO3)3 from LaCO3OH. Similarly, the same salt is formed when either material is dissolved in other aqueous acids. Because of the insolubility of La2(CO3)3 and LaCO3OH in standard solvents, and the fact that each substance reacts to form the same material in acidic solvents, chromatographic techniques such as HPLC cannot be used to develop quantitative methods to monitor the presence of degradants.
It is conceivable that dissolution in aqueous acid and titration of the resulting solution for lanthanum content could be a technique used to quantify the amount of LaCO3OH in La2(CO3)3 hydrate. However, this is impractical because the lanthanum content of both species is very similar. For example, LaCO3OH contains 64.3% La, La2(CO3)3 tetrahydrate contains 52.4% La, and a mixture of 1% LaCO3OH in La2(CO3)3 tetrahydrate would contain 52.5% La. Thus, one would be unable to distinguish pure pharmaceutical agent from pharmaceutical agents containing, for example, 1% degradant, which is an amount of degradant in excess of amounts typically allowed by regulations.
Various techniques might be used to develop quantitative analytical methods for analysis of solid mixtures. Examples of these techniques include differential scanning calorimetry, infrared spectroscopy, Raman spectroscopy, XRPD, solid-state nuclear magnetic resonance spectroscopy, and dynamic vapor sorption. The first criterion that must be met by an analytical technique to render it usable for method development is specificity. That is, the technique must be able to differentiate the analyte from the matrix (i.e. LaCO3OH from the pharmaceutical agent La2(CO3)3 hydrates and LaCO3OH from La2(CO3)3 hydrates when the sample additionally contains other excipients and/or carriers). However, most of these techniques are not capable of differentiating LaCO3OH from La2(CO3)3 hydrates.
A technique capable of differentiating LaCO3OH from La2(CO3)3 hydrates is x-ray powder diffraction (XRPD). Normally XRPD is a technique which is used to characterize materials and detect differences in crystal structure (such as polymorphs). It is therefore usually used in the identification of structures and is not normally used to quantify materials in the sense of an impurity or degradant assay.
Therefore, there is a need in the art to quantitatively determine the scope of material degradation and to quantifiably determine the level of purity of the degradation products of a rare earth compounds such as CaOHCO3 compared to the rare earth compound itself (i.e., La2(CO3)3).